DESCRIPTION (applicant's abstract): The methamphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) continues to be a popular drug of abuse despite evidence in animals and humans that this agent produces long-term toxicity to serotonin (5HT) neurons. However, beyond this well-established finding, the mechanisms through which MDMA produces 5HT neurotoxicity remains unknown. There is evidence that MDMA promotes oxidative stress through the increased formation of hydroxyl radicals and depletion of endogenous antioxidants. The intent of the present application is to elucidate the processes, subsequent to or preceding the generation of hydroxyl radicals, that are the determinants of MDMA-induced 5HT neurotoxicity. Moreover, it is our intent to relate the mechanisms of MDMA neurotoxicity to the functional consequences of the long-term depletion of brain 5HT. The overall hypothesis that provides the basis for these studies is that the MDMA-induced depletion of brain 5HT results from a) disruption of energy regulation, b) oxidative stress that promotes mitochondrial dysfunction and the cellular damage that accompanies these processes and c) that such damage results in impaired 5HT release and deficits in 5HT-mediated functional responses. To provide evidence in support of the roles of oxidative and metabolic stress in MDMA-induced 5HT neurotoxicity the specific aims are proposed to establish that 1) MDMA increases glycogenolysis and the formation of lactate and decreases the activity of mitochondrial enzymes, 2) MDMA toxicity is prevented by the administration of energy substrates and exacerbated by mitochondrial inhibitors, 3) prevention of MDMA-induced oxidative stress (e.g., hydroxyl radical formation ) offers protection against MDMA-induced mitochondrial impairment and 5HT neurotoxicity and 4) MDMA-induced oxidative and metabolic stress results in abnormal 5HT mediated functional responses, as manifested by abnormal thermal, neurochemical and behavioral responses to pharmacological agents or physiological conditions (e.g., stress). The linkage of the processes of oxidative damage and mitochondrial dysfunction with MDMA-induced toxicity to 5HT terminals has significant implications for drug-induced neurodegeneration and the consequences (i.e., risk) this may impose on the health of abusers of MDMA.